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Article: Carboxyl-terminal fragments of alzheimer β-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells
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TitleCarboxyl-terminal fragments of alzheimer β-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells
 
AuthorsChen, F2 3
Yang, DS2 3
Petanceska, S1
Yang, A1
Tandon, A2 3
Yu, G2 3
Rozmahel, R4 3
Ghiso, J1
Nishimura, M2 3
Zhang, DM2 3
Kawarai, T2 3
Levesque, G2 3
Mills, J2 3
Levesque, L2 3
Song, YQ2 3
Rogaeva, E2 3
Westaway, D2 3
Mount, H2 3
Gandy, S1
St GeorgeHyslop, P3 2
Fraser, PE2 3
 
Issue Date2000
 
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
 
CitationJournal Of Biological Chemistry, 2000, v. 275 n. 47, p. 36794-36802 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M006986200
 
AbstractAbsence of functional presenilin 1 (PS1) protein leads to loss of γ-secretase cleavage of the amyloid precursor protein (βAPP), resulting in a dramatic reduction in amyloid β peptide (Aβ) production and accumulation of α- or β-secretase-cleaved COOH-terminal fragments of βAPP (α- or β-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as αAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily Aβ-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length βAPP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of βAPP to the Golgi compartment is necessary before α- and β-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual γ-secretase catalytic activity or in other functions indirectly related to γ-secretase catalysis (e.g. an activator of γ-secretase, a substrate adaptor for γ-secretase, or delivery of γ-secretase to βAPP-containing compartments).
 
ISSN0021-9258
2012 Impact Factor: 4.651
2012 SCImago Journal Rankings: 2.723
 
DOIhttp://dx.doi.org/10.1074/jbc.M006986200
 
ISI Accession Number IDWOS:000165577700051
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorChen, F
 
dc.contributor.authorYang, DS
 
dc.contributor.authorPetanceska, S
 
dc.contributor.authorYang, A
 
dc.contributor.authorTandon, A
 
dc.contributor.authorYu, G
 
dc.contributor.authorRozmahel, R
 
dc.contributor.authorGhiso, J
 
dc.contributor.authorNishimura, M
 
dc.contributor.authorZhang, DM
 
dc.contributor.authorKawarai, T
 
dc.contributor.authorLevesque, G
 
dc.contributor.authorMills, J
 
dc.contributor.authorLevesque, L
 
dc.contributor.authorSong, YQ
 
dc.contributor.authorRogaeva, E
 
dc.contributor.authorWestaway, D
 
dc.contributor.authorMount, H
 
dc.contributor.authorGandy, S
 
dc.contributor.authorSt GeorgeHyslop, P
 
dc.contributor.authorFraser, PE
 
dc.date.accessioned2011-07-14T07:03:00Z
 
dc.date.available2011-07-14T07:03:00Z
 
dc.date.issued2000
 
dc.description.abstractAbsence of functional presenilin 1 (PS1) protein leads to loss of γ-secretase cleavage of the amyloid precursor protein (βAPP), resulting in a dramatic reduction in amyloid β peptide (Aβ) production and accumulation of α- or β-secretase-cleaved COOH-terminal fragments of βAPP (α- or β-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as αAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily Aβ-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length βAPP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of βAPP to the Golgi compartment is necessary before α- and β-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual γ-secretase catalytic activity or in other functions indirectly related to γ-secretase catalysis (e.g. an activator of γ-secretase, a substrate adaptor for γ-secretase, or delivery of γ-secretase to βAPP-containing compartments).
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationJournal Of Biological Chemistry, 2000, v. 275 n. 47, p. 36794-36802 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M006986200
 
dc.identifier.doihttp://dx.doi.org/10.1074/jbc.M006986200
 
dc.identifier.epage36802
 
dc.identifier.isiWOS:000165577700051
 
dc.identifier.issn0021-9258
2012 Impact Factor: 4.651
2012 SCImago Journal Rankings: 2.723
 
dc.identifier.issue47
 
dc.identifier.pmid10962005
 
dc.identifier.scopuseid_2-s2.0-0034711207
 
dc.identifier.spage36794
 
dc.identifier.urihttp://hdl.handle.net/10722/134763
 
dc.identifier.volume275
 
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Biological Chemistry
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAlzheimer Disease/metabolism
 
dc.subject.meshAmyloid Precursor Protein Secretases
 
dc.subject.meshAmyloid beta-Protein Precursor/*metabolism
 
dc.subject.meshAnimals
 
dc.subject.meshAspartic Acid Endopeptidases
 
dc.subject.meshBiological Markers
 
dc.subject.meshBrain/metabolism/ultrastructure
 
dc.subject.meshCell Compartmentation
 
dc.subject.meshElectrophoresis, Polyacrylamide Gel
 
dc.subject.meshEndopeptidases/metabolism
 
dc.subject.meshMembrane Proteins/deficiency/*physiology
 
dc.subject.meshMice
 
dc.subject.meshMice, Knockout
 
dc.subject.meshMicroscopy, Electron
 
dc.subject.meshPeptide Fragments/*metabolism
 
dc.subject.meshPresenilin-1
 
dc.titleCarboxyl-terminal fragments of alzheimer β-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells
 
dc.typeArticle
 
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<item><contributor.author>Chen, F</contributor.author>
<contributor.author>Yang, DS</contributor.author>
<contributor.author>Petanceska, S</contributor.author>
<contributor.author>Yang, A</contributor.author>
<contributor.author>Tandon, A</contributor.author>
<contributor.author>Yu, G</contributor.author>
<contributor.author>Rozmahel, R</contributor.author>
<contributor.author>Ghiso, J</contributor.author>
<contributor.author>Nishimura, M</contributor.author>
<contributor.author>Zhang, DM</contributor.author>
<contributor.author>Kawarai, T</contributor.author>
<contributor.author>Levesque, G</contributor.author>
<contributor.author>Mills, J</contributor.author>
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<contributor.author>Song, YQ</contributor.author>
<contributor.author>Rogaeva, E</contributor.author>
<contributor.author>Westaway, D</contributor.author>
<contributor.author>Mount, H</contributor.author>
<contributor.author>Gandy, S</contributor.author>
<contributor.author>St GeorgeHyslop, P</contributor.author>
<contributor.author>Fraser, PE</contributor.author>
<date.accessioned>2011-07-14T07:03:00Z</date.accessioned>
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<date.issued>2000</date.issued>
<identifier.citation>Journal Of Biological Chemistry, 2000, v. 275 n. 47, p. 36794-36802</identifier.citation>
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<description.abstract>Absence of functional presenilin 1 (PS1) protein leads to loss of &#947;-secretase cleavage of the amyloid precursor protein (&#946;APP), resulting in a dramatic reduction in amyloid &#946; peptide (A&#946;) production and accumulation of &#945;- or &#946;-secretase-cleaved COOH-terminal fragments of &#946;APP (&#945;- or &#946;-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as &#945;APP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily A&#946;-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length &#946;APP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of &#946;APP to the Golgi compartment is necessary before &#945;- and &#946;-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual &#947;-secretase catalytic activity or in other functions indirectly related to &#947;-secretase catalysis (e.g. an activator of &#947;-secretase, a substrate adaptor for &#947;-secretase, or delivery of &#947;-secretase to &#946;APP-containing compartments).</description.abstract>
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<subject.mesh>Amyloid Precursor Protein Secretases</subject.mesh>
<subject.mesh>Amyloid beta-Protein Precursor/*metabolism</subject.mesh>
<subject.mesh>Animals</subject.mesh>
<subject.mesh>Aspartic Acid Endopeptidases</subject.mesh>
<subject.mesh>Biological Markers</subject.mesh>
<subject.mesh>Brain/metabolism/ultrastructure</subject.mesh>
<subject.mesh>Cell Compartmentation</subject.mesh>
<subject.mesh>Electrophoresis, Polyacrylamide Gel</subject.mesh>
<subject.mesh>Endopeptidases/metabolism</subject.mesh>
<subject.mesh>Membrane Proteins/deficiency/*physiology</subject.mesh>
<subject.mesh>Mice</subject.mesh>
<subject.mesh>Mice, Knockout</subject.mesh>
<subject.mesh>Microscopy, Electron</subject.mesh>
<subject.mesh>Peptide Fragments/*metabolism</subject.mesh>
<subject.mesh>Presenilin-1</subject.mesh>
<title>Carboxyl-terminal fragments of alzheimer &#946;-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells</title>
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Author Affiliations
  1. New York University School of Medicine
  2. Toronto General Hospital
  3. University of Toronto
  4. Hospital for Sick Children University of Toronto